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Journal of the National Cancer Institute 103 (13): 1018-1036 (2011-07-06)

Sack U.; Walther W.; Scudiero D.; Selby M.; Kobelt D.; Lemm M.; Fichtner I.; Schlag P.M.; Shoemaker R.H.; Stein U.

Novel effect of antihelminthic niclosamide on S100A4-mediated metastatic progression in colon cancer

Background: Metastasis formation in colon cancer severely reduces the survival rate in patients. S100A4, a calcium-binding protein, is implicated in promoting metastasis formation in colon cancer. Methods: To identify a transcription inhibitor of S100A4, high-throughput screening of 1280 pharmacologically active compounds was performed using a human colon cancer cell line expressing a S100A4 promoter-driven luciferase (LUC) reporter gene construct (HCT116-S1004p-LUC). Niclosamide, an antihelminthic agent, was identified as a potential candidate. Colon cancer cell lines (HCT116, SW620, LS174T, SW480, and DLD-1) were treated with 1 muM niclosamide to analyze the effect on S100A4 mRNA and protein expression by quantitative reverse transcription-polymerase chain reaction and immunoblot assays, and effects on cell migration, invasion, proliferation, and colony formation were also assessed in vitro. The effect of niclosamide on liver metastasis was assessed in a xenograft mouse model of human colon cancer (n = 8 mice) by in vivo imaging. The long-term effect of niclosamide on metastasis formation after discontinued treatment was quantified by scoring, and overall survival (n = 12 mice) was analyzed by Kaplan-Meier method after discontinuation of treatment. All statistical tests were two-sided. Results: Reduced S100A4 mRNA and protein expression, and inhibited cell migration, invasion, proliferation, and colony formation were observed in niclosamide-treated colon cancer cells in vitro. In vivo imaging of niclosamide-treated mice showed reduced liver metastasis compared with solvent-treated control mice (n = 4 mice per group). Compared with the control group, discontinuation of treatment for 26 days showed reduced liver metastasis formation in mice (n = 6 mice per group) (control vs discontinuous treatment, mean metastasis score = 100% vs 34.9%, mean difference = 65.1%; 95% confidence interval [CI] = 18.4% to 111.9%, P < .01) and increased overall survival (n = 6 mice per group; control vs discontinuous treatment, median survival = 24 vs 46.5 days, ratio = 0.52, 95% CI = 0.19 to 0.84, P = .001). Conclusion: Niclosamide inhibits S100A4-induced metastasis formation in a mouse model of colon cancer and has therapeutic potential.

Keywords: Mice, Animals, Wnt Proteins, Tumor Stem Cell Assay, Tumor Cell Line, Heterologous Transplantation, Time Factors, Signal Transduction, SCID Mice, S100 Proteins, Reverse Transcriptase Polymerase Chain Reaction, Random Allocation, Prognosis, Parenteral Infusions, Niclosamide, Neoplastic Gene Expression Regulation, Neoplasm RNA, Neoplasm Invasiveness, Messenger RNA, Liver Neoplasms, Kaplan-Meier Estimate, Inbred NOD Mice, Immunoblotting, Electrophoretic Mobility Shift Assay, Disease Progression, Colonic Neoplasms, Chromatin Immunoprecipitation, Cell Proliferation, Cell Movement, Biological Tumor Markers, beta Catenin, Antineoplastic Agents, Anthelmintics

Type: Article

PubMed: 21685359
Official URL: https://doi.org/10.1093/jnci/djr190
MDC Repository: https://edoc.mdc-berlin.de/11723/